PROGESTERONE ANTAGONIST RU-486 HAS BONE-SPARING EFFECTS IN OVARIECTOMIZED RATS

We demonstrated previously that progesterone prevents ovariectomy-indu ced bone loss. RU 486 is a synthetic steroid with antiprogesterone act ivities in reproductive tissue. We used 12-week-old rats to evaluate e ffects of RU 486 in sham-operated rats and to compare medroxyprogester one (MPA), RU 486, and medroxyprogesterone plus RU 486 combined treatm ent in ovariectomized rats. Ovariectomized rats were treated with MPA (60 mg/kg intramuscularly), RU 486 (10 mg/kg/day subcutaneously every 4 days), both, or vehicle. Sham-operated rats were treated with simila r doses of RU 486 or vehicle. After 4 weeks of treatment the rats were sacrificed and bone histomorphometry was performed on proximal tibial metaphysis. Trabecular bone volume was lower (33.9 +/- 1.5% vs. 46.3 +/- 1.4%) and bone turnover was higher in ovariectomized than in sham- operated rats. The fraction of trabecular bone in OVX rats treated wit h MPA, RU 486, or both were 41.6 +/- 2.5%, 44.8 +/- 2.8%, and 38.4 +/- 1.4%, respectively. Medroxyprogesterone treatment tended to preserve bone mass by inhibiting the increased resorption indices while maintai ning higher formation rates seen in ovariectomized rats. The effects o f RU 486 were similar to those of medroxyprogesterone, suggesting an a gonist-like effect. Medroxyprogesterone effects were attenuated when i t was combined with RU 486, suggesting that RU 486 acted as a partial antagonist in the presence of exogenous progesterone. Bone parameters were less affected in sham-operated RU 486-treated rats, and there was no significant change in bone volume (43.2 +/- 1.7%). Thus, RU 486 mi micked the effects of progesterone on trabecular bone in ovariectomize d rats when given alone, but acted as a partial antagonist when admini stered together with progesterone.